Photoactivation or Photosensitization is a process in which a photosensitive substance activated or excited by energy provided by light or heat forms a highly reactive molecule that transfers its energy (e.g., hydrogen or electron) to other molecules during its return to the unactivated or unexcited state (decay). Transfer of hydrogen or electron to oxygen can form free radical or singlet oxygen, for example, as well as reactive decay intermediates, which subsequently react with or otherwise modify other components. Photooxidizing agents are a particular type of photosensitive agent that forms reactive molecules which oxidize components, and generally function by either of two pathways as shown below: Type (1) activated photooxidizing agent (3D) reacts with oxygen (hydrogen or electron transfer) to produce a positive agent radical and free radical oxygen. The positive agent radical reacts with guanine, for example, and the free radical oxygen can react with other organic components. Type (2) activated photooxidizing agent (3D) transfers energy to oxygen to produce singlet oxygen which subsequently reacts with cell components such as guanine, for example.    Type (1): 3D+02 D++02− D++G D+G+    Type (2): 3D+02 D+102 102+G 02−+G+
Where: D, 3D—dye and its triplet (activated or excited) state; G, G+—guanine as substrate, its radical splits the DNA backbone; and 02, 102, 02−—oxygen, its single state, its radical.
Photosensitive agents have been used for killing cells since the beginning of the century. Photooxidation by natural and synthetic agents has been used experimentally for the destruction of diseased tissue and cancer (Kessel D, Photochem. Photobiol. 44:489 (1986); Bottiroli et al., Photochem. Photobiol. 47:209 (1988); G. Jori and C. Perria (eds), Photodynamic Therapy of tumors and other diseases, Libreria Progetta Editore, Padova, 1985; Berg et al., J. Naturwiss. 53:481 (1966); Koston et al., J. Photochem. Photobiol. B 36:157 (1996); Berg, H., J. Photochem. Photobiol. 28:399 (1988); Kennedy et al., U.S. Pat. No. 5,079,262). The photodynamic destruction (photodynamic therapy) of tumors nowadays is one of the more effective methods in cancer therapy (G. Jori and C. Perria (eds), 1985 supra; Koston et al., supra (1996)). Hyperthermia, or heat increases the reaction rate of the photooxidizing agent thereby increasing photodynamic destruction (Kimel et al., J. Laser Surg. Med. 12:432 (1992)). However, systemic administration of photooxidizing agents usually is associated with nonselective cell killing. Furthermore, many agents are relatively insoluble making their in vivo usefulness limited.
The cell membrane may be transiently permeabilized by subjecting cells to a brief, high intensity, electric field. This electrically-induced permeabilization of cell membranes, termed electroporation, has been used by investigators to introduce various compositions such as drugs, DNA, RNA, proteins, liposomes, latex beads, whole virus particles and other macromolecules into living mammalian cells (Berg et al., Electric field effects on biological membranes: electroincorporation and electrofusion In: Bioelectrochemistry II, Membrane Phenomena (Eds. R. G. Milazzo, M. Blank) Plenum Press, N.Y., London, p. 135–1661 (1987); Lehmann et al., Bioelectrochem. Bioenerg. 41:227–229 (1996); Hapala, Crit. Rev. Biotechnol. 17:105 (1997); Eanault et al., Gene 144:205 (1994); Chu et al., Nucl. Acids Res. 15:1311 (1987); Knutson et al., Anal. Biochem. 164:44 (1987); Gibson et al., EMBO J. 6:2457 (1987); Dower et al., Genetic Engineering 12:275 (1990); Mozo et al., Plant Molecular Biology 16:917 (1991)). These studies show that electroporation affords an efficient means to deliver therapeutic compositions such as drugs, genes, polypeptides and the like in vivo by applying an electrical pulse to particular cells, tissues or organs within a subject.
Therapeutic applications of electroporation are now being explored: introduction of functional genes for gene therapy (Nishi et al., Cancer Research 56:1050 (1996)); electroporation of skin for the delivery of drugs into the skin or for the transdermal delivery of drugs across tissue (Zhang et al., Biochem. Biophys. Res. Comm. 220:633(1996)), Weaver et al., U.S. Pat. No. 5,019,034 and Prausnitz, Adv. Drug. Deliv. 18:395 (1996)); angioplasty combined with electroporation to deliver drugs to a localized portion of coronary or peripheral arteries has been used to treat restenosis (Shapland et al., U.S. Pat. No. 5,498,238); cancer treatment by electroporation in the presence of low doses of chemotherapeutic drugs (Mir, U.S. Pat. No. 5,468,223). Particular apparatus for in vivo electroporation have been developed to effect treatment: Hofmann describes a syringe apparatus for electroporating molecules and macromolecules into tissue regions in vivo in which the needles of the syringe used to deliver the molecules also function as electroporation electrodes (U.S. Pat. No. 5,273,525). Weaver describes an electroporation apparatus for the delivery of chemical agents into tissues in vivo (U.S. Pat. No. 5,389,069). Hofmann et al., describe an electroporation catheter device useful for delivering genes or drugs to treat endothelial and other cells of blood vessels, for example (U.S. Pat. No. 5,507,724). Crandell et al. describe an electroporation catheter apparatus useful for introducing therapeutic macromolecules into endothelial cells of a patients blood vessels (U.S. Pat. No. 5,304,120).
Although numerous efforts have been directed to developing new therapeutic approaches to cancer treatment, cancer continues to be one of the more vexing cell proliferative disorders affecting mankind. Thus, a need exists for the development of new methods and apparatus for treating cancer and other cell proliferative disorders. The present invention satisfies this need and provides related advantages as well.